Environmental risks of chemicals are still often assessed substance-by-substance, neglecting mixture effects. This may result in risk underestimations, as the typical exposure is toward multicomponent chemical "cocktails". We use the two well established mixture toxicity concepts (Concentration Addition (CA) and Independent Action (IA)) for providing a tiered outline for environmental hazard and risk assessments of mixtures, focusing on general industrial chemicals and assuming that the "base set" of data (EC50s for algae, crustaceans, fish) is available. As mixture toxicities higher than predicted by CA are rare findings, we suggest applying CA as a precautious first tier, irrespective of the modes/mechanisms of action of the mixture components. In particular, we prove that summing up PEC/PNEC ratios might serve as a justifiable CA-approximation, in order to estimate in a first tier assessment whether there is a potential risk for an exposed ecosystem if only base-set data are available. This makes optimum use of existing single substance assessments as more demanding mixture investigations are requested only if there are first indications of an environmental risk. Finally we suggest to call for mode-of-action driven analyses only if error estimations indicate the possibility for substantial differences between CA- and IA-based assessments.

Background: Only recently has the environment been clearly implicated in the risk of antibiotic resistance to clinical outcome, but to date there have been few documented approaches to formally assess these risks.Objective: We examined possible approaches and sought to identify research needs to enable human health risk assessments (HHRA) that focus on the role of the environment in the failure of antibiotic treatment caused by antibiotic-resistant pathogens.Methods: The authors participated in a workshop held 4–8 March 2012 in Québec, Canada, to define the scope and objectives of an environmental assessment of antibiotic-resistance risks to human health. We focused on key elements of environmental-resistance-development “hot spots,” exposure assessment (unrelated to food), and dose response to characterize risks that may improve antibiotic-resistance management options.Discussion: Various novel aspects to traditional risk assessments were identified to enable an assessment of environmental antibiotic resistance. These include a) accounting for an added selective pressure on the environmental resistome that, over time, allows for development of antibiotic-resistant bacteria (ARB); b) identifying and describing rates of horizontal gene transfer (HGT) in the relevant environmental “hot spot” compartments; and c) modifying traditional dose–response approaches to address doses of ARB for various health outcomes and pathways.Conclusions: We propose that environmental aspects of antibiotic-resistance development be included in the processes of any HHRA addressing ARB. Because of limited available data, a multicriteria decision analysis approach would be a useful way to undertake an HHRA of environmental antibiotic resistance that informs risk managers.Citation: Ashbolt NJ, Amézquita A, Backhaus T, Borriello P, Brandt KK, Collignon P, Coors A, Finley R, Gaze WH, Heberer T, Lawrence JR, Larsson DG, McEwen SA, Ryan JJ, Schönfeld J, Silley P, Snape JR, Van den Eede C, Topp E. 2013. Human health risk assessment (HHRA) for environmental development and transfer of antibiotic resistance. Environ Health Perspect 121:993–1001; http://dx.doi.org/10.1289/ehp.1206316

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Abstract-A promising tool for the risk assessment of chemical mixtures is the prediction of their toxicities from the effects of the individual components. For that purpose, concentration addition is uniformly regarded as valid for mixtures of similarly acting chemicals. Whether this concept or the competing notion of independent action is more appropriate for mixtures of dissimilarly acting chemicals is still in dispute. Therefore, the presented study analyzed and compared the predictive capabilities of both concepts for a multiple mixture designed of strictly dissimilarly acting compounds. Experimental investigations were conducted using a longterm bioluminescence inhibition assay with Vibrio fischeri. Results show an excellent predictive power of independent action, while concentration addition overestimates the mixture toxicity. Thus, the precise prediction of mixture toxicities depends on a valid assessment of the similarity/dissimilarity of the mixture components. However, concentration addition underestimates the EC50 of the mixture only by a factor of less than three. As the similarity of components is often unknown for mixtures found in the environment, it is concluded that concentration addition may give a realistic worst case estimation of mixture toxicities for risk assessment procedures.

Existing environmental risk assessment procedures are limited in their ability to evaluate the combined effects of chemical mixtures. We investigated the implications of this by analyzing the combined effects of a multicomponent mixture of five estrogenic chemicals using vitellogenin induction in male fathead minnows as an end point. The mixture consisted of estradiol, ethynylestradiol, nonylphenol, octylphenol, and bisphenol A. We determined concentration–response curves for each of the chemicals individually. The chemicals were then combined at equipotent concentrations and the mixture tested using fixed-ratio design. The effects of the mixture were compared with those predicted by the model of concentration addition using biomathematical methods, which revealed that there was no deviation between the observed and predicted effects of the mixture. These findings demonstrate that estrogenic chemicals have the capacity to act together in an additive manner and that their combined effects can be accurately predicted by concentration addition. We also explored the potential for mixture effects at low concentrations by exposing the fish to each chemical at one-fifth of its median effective concentration (EC50). Individually, the chemicals did not induce a significant response, although their combined effects were consistent with the predictions of concentration addition. This demonstrates the potential for estrogenic chemicals to act additively at environmentally relevant concentrations. These findings highlight the potential for existing environmental risk assessment procedures to underestimate the hazard posed by mixtures of chemicals that act via a similar mode of action, thereby leading to erroneous conclusions of absence of risk.

Abstract-The prediction of combined effects based on the effects of the individual components of mixtures by using the pharmacological concepts of concentration addition and independent action might be a promising tool for the risk assessment of pollutant mixtures. To analyze and compare the predictive capabilities of the reference concepts for similarly acting chemicals, the overall toxicity of a multiple mixture was determined in a bioluminescence inhibition assay with Vibrio fischeri. The mixture was composed of 16 similarly and specifically acting chemicals, anticipated to have a common mode of action via weak acid respiratory uncoupling of oxidative phosphorylation. Results show that the observed mixture toxicity is rather well predicted by both concepts. Concentration addition shows an excellent predictive power; the median effective concentration (EC50) of the mixture is predicted with an error of about 10%. Independent action, in contrast, underestimates the EC50 of the mixture by a factor of a little more than three. With respect to risk assessment procedures, it may be concluded that concentration addition gives a valid estimation of the overall toxicity for multiple mixtures with similar and specific mechanisms of action of the mixture components in this type of biotest.